ABSTRACT Hepatocellular carcinoma (HCC) is one of the most common malignancy, representing more than 5% of all cancers, and its incidence is rising rapidly worldwide. The only curative therapies are resection, liver transplantation, and a few pharmaceutical interventions to delay its onset. However, the recurrence of HCC and its metastasis is very common and rapid. Thus, there is an unmet medical need for development of therapeutic agents for prevention and treatment of HCC. Atiprimod is an anti-cancer and anti-angiogenic compound, which is currently in clinical evaluations in liver carcinoid tumor patients. Early observations from these clinical trials indicate a clear cut reduction in disease symptoms. However, orally administered drug was poorly observed, resulting in dose-limiting GI toxicities due to its accumulation in the gut. This is consistent with the ADME results indicating that only 12% of the orally administered atiprimod was systemically absorbed, and about 68% remained in the gut for upto 168 h. The poor systemic absorption of atiprimod could be attributed to its high protein-binding property. Interestingly, atiprimod preferentially inhibited proliferation and induced apoptosis, through deactivation of PI-3 kinase/Akt and Jak/STAT3 pathways, in HCC cells that expressed either hepatitis B (HBV) or hepatitis C (HCV). Thus, analogs of atiprimod with superior potency and better systemic absorption could be developed as drug candidates to control and treat HCC in humans. Thus, the specific aims are: 1. to design novel analogs of atiprimod, based on computational analysis of the pharmacophore group and the side chains, to improve systemic absorption as well as to increase potency. The synthesized compounds will be tested for their potencies in cell proliferation assays and for their abilities to inhibit activation of Akt and STAT3. 2. To evaluate lead compounds for their effect on HBV/HCV gene expression in HCC cells. 3. Finally, the best leads will be evaluated in an orthotropic model involving implantation of HCC cells in liver. Thus, successful completion of the proposed research is expected to result in novel compounds that can be further evaluated in Woodchucks and in transgenic mice model of HCC, as part of the planned STTR phase II grant application. The proposed STTR Phase I proposal is based on the recent finding that atiprimod is a potent inhibitor of PI-3K/Akt and Jak-STAT-3 signaling pathways, which are often upregulated in a variety of human cancers. In addition, atiprimod also preferentially kills HCC cells that express HBV and HCV viruses, which are known to be the major culprits for HCC development in humans. Early observations from a Phase I clinical trial in liver carcinoid patients is very encouraging and warrant development of analogs of atiprimod with better potency and higher systemic absorption from the gut. Our plan to design analogs is based on the computer modeling-guided modifications in the pharmacophore group to fix the existing two chiral centers and to modify hydrophobic side chains to reduce protein-binding. Compounds will be evaluated in cell-based assays to identify leads with superior potencies. The best candidate will then be evaluated for their efficacies in HCC animal model. Successful completion of the proposed research will have identified a new drug candidate that can be further developed for prevention and treatment of HBV/HCV induced liver diseases and/or HCC in humans.